What is Epigenomics?
What makes them different?
Much human variation is due to difference in ~6 million DNA base pairs (0.1% of genome)
- Phenotype, including disease susceptibility
- One led a fairly strict diet and regimen, had pancreatic cancer, the other did not
- While that gives a lot of information about the molecular basis of certain processes, it is not the full story.
What makes them different?
Genes are expressed differently during different stages and in different tissues.
- Something that we want to understand is how that genetic variation leads to phenotypic variation.
- A major part of understanding that, comes from understanding how regulation works.
DNA is packed, making certain parts inaccessible, and this packing is dynamic.
- DNA structure plays a major role
DNA methylation is a chemical modification of DNA, involved in gene expression regulation.
- DNA methylation plays a major role in this regulation process
- Plus, we know how it is inherited from cell to cell, cell-fate
- invovled in differentiation
- can give us an important idea of this process in development and disease
- plasticity
Probing DNA Methylation
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Probing DNA Methylation
- Local-likelihood smoothing method
- high-frequency smoothing reveals local methylation structure (small domains)
- low-frequency smoothing reveals long-range methylation structure (large domains)
DNA Methylation in cancer
Large blocks of *hypo-methylation in colon cancer
- long,
- consistent but partially methylated in normal tissues
- while methylation levels are inconsistent in cancer, boundaries of these domains are conserved across tissues
- overlaps with other important genomic domains
- genes within these blocks are tissue-specific
Genes with hyper-variable expression in colon cancer are enriched within these blocks.
Hypo-methylation blocks observed in other cancer types.
Gene expression hyper-variability enriched in hypo-methylation blocks in other cancer types.
Genes with consistent hyper-variable expression across tumors are tissue-specific.
Summary
- Large domains of methylation loss is a stable mark across different cancer types
- Gene expression hyper-variability is enriched within these domains
- Genes within these regions are tissue-specific and involved in cellular fate
Genes are expressed differently during different stages and in different tissues.